Starve and Kill: Engineered Antigens Targeting Nutrient Acquisition Pathways Essential for Gonococcal Infection and Disease

挨饿和杀死：针对淋球菌感染和疾病所必需的营养获取途径的工程抗原

• 批准号: 10355467
• 负责人: CYNTHIA N CORNELISSEN
• 金额: $ 180.61万
• 依托单位: GEORGIA STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-03-25 至 2024-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10355467
• 关键词: Adjuvant; Animals; Antibiotics; Antibodies; Antigen Targeting; Antigenic Diversity; Antigens; Bacteria; Binding; Binding Proteins; Centers for Disease Control and Prevention (U.S.); Characteristics; Clinical; Communities; Community Outreach; Computer Models; Data; Detection; Development; Disease; Drug resistance; Economics; Engineering; Exhibits; Female genitalia; Formulation; Funding; Future; Genetic; Genomics; Goals; Gonorrhea; Growth; Heterogeneity; Human; Immune; Immune response; Immunity; Immunize; In Transferrin; Infection; Infection prevention; Iron; Life; Life Style; Ligand Binding; Ligands; Mediating; Membrane; Membrane Proteins; Metals; Misinformation; Modeling; Morbidity - disease rate; Names; Neisseria gonorrhoeae; Nutrient; Nutritional Immunity; Pathway interactions; Pharmaceutical Preparations; Pharmacotherapy; Phenotype; Population; Prevalence; Process; Proteins; Public Health; Research; Resistance; Risk; Serum Proteins; Sexual Partners; Sexually Transmitted Agents; Sexually Transmitted Diseases; Site; Superbug; Surface; Surface Antigens; Symptoms; System; TFRC gene; Target Populations; Testing; Tissues; Trace metal; Transferrin; Vaccine Antigen; Vaccines; Virulent; Zinc; antimicrobial drug; base; clinically relevant; cross immunity; epidemiologic data; gonorrhea vaccine; human pathogen; human tissue; humanized mouse; immunogenic; implementation strategy; improved; innovation; international center; mathematical model; microbial; mouse model; mutant; novel; nutrient deprivation; pathogen; prevent; programs; receptor; reproductive tract; resistance factors; response; sex; success; translational research program; transmission process; trend; uptake; vaccine acceptance; vaccine development; vaccine discovery; vaccine formulation; vaccine hesitancy

Abstract/Summary Neisseria gonorrhoeae has re-emerged as a global public health concern as it causes roughly 100 million new infections each year and isolates have emerged that are resistant to all clinically-relevant antibiotics; these alarming trends have prompted the US Center for Disease Control to name N. gonorrhoeae as one of three `urgent' microbial threats. The success of N. gonorrhoeae is attributable in part to its capacity to colonize the female genital tract without obvious clinical manifestation, allowing it to persist undetected as it is spread to sexual partners. Consistent with this, N. gonorrhoeae does not express factors with overt virulent potential. Instead, it exhibits a lifestyle intent on avoiding and actively subverting immune detection, and expresses elegant systems to access highly restricted nutrient stores to support its growth within human tissues. This translational research program will exploit our recent success in targeting the receptor proteins that allow N. gonorrhoeae to acquire iron and zinc during infection; these trace metals are essential for life but effectively absent in mammalian tissues due to a process known as `nutritional immunity'. We have unexpectedly discovered that the bacterial surface-exposed receptor proteins that bind the host iron sequestering-serum protein transferrin does not elicit a protective immune response because it rapidly binds transferrin in the tissues, and that we can overcome this deficit by generating a point mutant that is structurally identical except that it does not bind transferrin. We will use this approach to generate immunogens that target alternative iron and zinc acquisition systems of N. gonorrhoeae, and then produce a multicomponent vaccine that elicits an immune response that will simultaneously starve the bacteria of these two essential nutrients and kill the bacteria through classical antibody-dependent activities. Along with this directly translational pursuit, we will also perform community outreach studies to understand the potential resistance to gonococcal vaccines among different stakeholder populations and reveal potential strategies to overcome these barriers. Then, our genomic and phenotypic analysis of the global diversity of the receptor systems that we are targeting will be integrated with global gonococcal epidemiology data and the understanding gained through our community-based studies to make informed predictions about the potential impact of different vaccine formulation and public health-focused implementation strategies on the global prevalence of N. gonorrhoeae. When complete, this program will therefore deliver a vaccine formulation that targets distinct but equally essential nutrient uptake pathways to confer sterilizing immunity against gonococcal infection and will provide actionable information that will guide the eventual implementation of this vaccine in a manner that will ultimately allow eradication of this devastating human-restricted pathogen.

摘要/总结 淋病奈瑟菌已重新成为全球公共卫生问题，因为它导致约 1 亿人死亡 每年都会出现感染，并且出现对所有临床相关抗生素具有抗药性的分离株；这些 令人震惊的趋势促使美国疾病控制中心将淋病奈瑟菌列为三大致病菌之一 “紧急”的微生物威胁。淋病奈瑟菌的成功部分归因于其定殖于 女性生殖道没有明显的临床表现，因此在传播到女性生殖道时无法被发现。 性伴侣。与此一致的是，淋病奈瑟菌不表达具有明显毒性潜力的因子。 相反，它展现了一种旨在避免并主动颠覆免疫检测的生活方式，并表达了优雅的气质。 系统获取高度受限的营养储备，以支持其在人体组织内的生长。这个翻译 研究计划将利用我们最近在靶向受体蛋白方面取得的成功，使淋病奈瑟菌能够 感染期间获取铁和锌；这些微量金属对于生命至关重要，但在哺乳动物中实际上不存在 由于称为“营养免疫”的过程而产生的组织。我们意外地发现，细菌 结合宿主铁隔离血清蛋白的表面暴露受体蛋白转铁蛋白不会引起 保护性免疫反应，因为它能快速结合组织中的转铁蛋白，我们可以克服这个问题 通过产生结构相同但不结合转铁蛋白的点突变体来弥补缺陷。我们将 使用这种方法生成针对 N.N. 替代铁和锌获取系统的免疫原。 淋病，然后生产一种多成分疫苗，引发免疫反应， 同时使细菌缺乏这两种必需营养素，并通过经典方法杀死细菌 抗体依赖性活动。除了这种直接转化的追求之外，我们还将开展社区活动 进行外展研究，以了解不同利益相关者对淋球菌疫苗的潜在耐药性 人口并揭示克服这些障碍的潜在策略。然后，我们的基因组和表型 我们针对的受体系统的全球多样性分析将与全球整合 淋球菌流行病学数据和通过我们基于社区的研究获得的理解 对不同疫苗配方和公共卫生重点的潜在影响进行明智的预测 关于淋病奈瑟菌全球流行的实施战略。完成后，该程序将 因此，提供一种针对不同但同样重要的营养吸收途径的疫苗配方 赋予针对淋球菌感染的灭菌免疫力，并将提供可操作的信息来指导 最终以一种最终能够根除这种毁灭性病毒的方式实施这种疫苗 人类限制的病原体。